Contrast media for ultrasonic imaging

ABSTRACT

Novel contrast media for use in ultrasonic imaging are described. Such contrast media may be comprised of an aqueous solution of one or more biocompatible polymers, wherein said biocompatible polymers are coated with and/or in admixture with at least one silicon containing compound. Alternatively, the contrast media may be comprised of an aqueous solution of one or more biocompatible synthetic polymers, or an aqueous solution of cellulose. The contrast media may be employed, if desired, with anti-gas agents and/or suspending agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 058,098, filed May 5,1993, now U.S. Pat. No. 5,420,176, which in turn is a continuation ofU.S. Ser. No. 708,731, filed on May 31, 1991, now abandoned, which inturn is a continuation-in-part application of U.S. Ser. No. 532,213,filed on Jun. 1, 1990, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of ultrasonic imaging, and morespecifically to the use of polymers as contrast agents for ultrasonicimaging.

2. Description of the Prior Art

There are a variety of imaging techniques that have been used todiagnose disease in humans. One of the first imaging techniques employedwas X-rays. In X-rays, the images produced of the patient's body reflectthe different densities of body structures. To improve the diagnosticutility of this imaging technique, contrast agents are employed in anattempt to increase the differences in density between variousstructures, such as between the gastrointestinal tract and itssurrounding tissues. Barium and iodinated contrast material, forexample, are used extensively for X-ray gastrointestinal studies tovisualize the esophagus, stomach, intestines and rectum. Likewise, thesecontrast agents are used for X-ray computed tomographic studies toimprove visualization of the gastrointestinal tract and to provide, forexample, contrast between the tract and the structures adjacent to it,such as the vessels or the lymph nodes. Such gastrointestinal contrastagents permit one to increase the density inside the esophagus, stomach,intestines and rectum, and allow differentiation of the gastrointestinalsystem from surrounding structures.

Ultrasound is a more recent imaging technique which, unlike X-rays, doesnot utilize ionizing radiation. Instead, in ultrasound, sound waves aretransmitted into a patient. These sound waves are then reflected fromtissue in the patient and are received and processed to form an image.Since ultrasound does not employ ionizing radiation to produce theseimages, ultrasound is less invasive and safer to the patient than X-rayimaging techniques. Ultrasound, however, suffers at times in imagingclarity in comparison to X-rays, particularly where imaging of thegastrointestinal tract is involved. In ultrasound, one major problem isthe presence of air/fluid interfaces, which results in shadowing of theultrasound beam. Shadowing, in turn, prevents the ultrasound beam frompenetrating beyond the air/fluid interface, and thus preventsvisualization of structures near any air pockets. Another problem withultrasound is the difficulty in imaging adjacent hypoechoic structures,that is, structures that are only minimally reflective of the ultrasoundbeam and, therefore, result in a low ultrasound signal. These problemsare particularly evident in the gastrointestinal region, with its manyair/liquid interfaces and its adjacent fluid-filled mucosal lining andoften fluid-containing lumen. If better contrast agents were availablefor ultrasound, the diagnostic accuracy and the overall usefulness ofultrasound as an imaging modality, particularly in the gastrointestinalregion, would be greatly enhanced.

In the past, investigators have attempted to solve the problemsassociated with gastrointestinal ultrasonic imaging by using water tofill the gastrointestinal tract. Water, however, was found to simply mixwith the gas, and thus much of the shadowing resulting from the presenceof air/fluid interfaces remained. In addition, the fact that water isabsorbed by the bowel decreased its ability to serve any meaningfulcontrast enhancement function distally within the tract. Furthermore,the water is hypoechoic, and its presence adjacent to the fluid-filledhypoechoic mucosal lining of this region resulted in littledifferentiation of the tract lumen and from its lining. Intravenouslyadministered glucagon has been employed in connection with suchgastrointestinal imaging, since glucagon administered in this fashionrelaxes the bowel by decreasing peristalsis. Although a helpfulultrasound adjunct, this, however, does not address such problems asshadowing caused by air/fluid interfaces and low differentiation causedby the presence of adjacent hypoechoic structures.

The need is great for contrast agents useful in ultrasonic imaging ofvarious regions of the body, particularly those useful in imaging thegastrointestinal tract. The present invention is directed to theseimportant ends.

SUMMARY OF THE INVENTION

The present invention is directed to a contrast medium useful forultrasonic imaging.

Specifically, the invention pertains to a contrast medium comprising anaqueous solution of at least one biocompatible polymer, wherein saidbiocompatible polymer is coated with and/or in admixture with at leastone silicon containing compound.

The invention also pertains to a contrast medium comprising an aqueoussolution of at least one biocompatible synthetic polymer.

The invention further pertains to a contrast medium comprising anaqueous solution of cellulose.

Further, the subject invention encompasses a method of providing animage of an internal region of a patient, especially an image of thegastrointestinal region of the patient, said method comprising (i)administering to the patient one or more of the aforementioned contrastmedia, and (ii) scanning the patient using ultrasonic imaging to obtainvisible images of the region.

Still further, the present invention comprises a method for diagnosingthe presence of diseased tissue in a patient, especially in thegastrointestinal region of the patient, said method comprising (i)administering to the patient one or more of the foregoing contrastmedia, and (ii) scanning the patient using ultrasonic imaging.

Finally, the present invention contemplates kits including the foregoingcontrast media.

The present ultrasound contrast agents are particularly useful whenemployed in the gastrointestinal region, serving to improvevisualization by displacing gas within the tract and providing contrastto the bowel lumen by filling it with material which has an echogenicitydifferent from the adjacent mucosa.

These and other aspects of the invention will become more apparent fromthe following detailed description when taken in conjunction with thefollowing drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic view of a portion of the gastrointestinal tractof a patient showing representative air and fluid levels and air bubblesnaturally present in the stomach and small intestines.

FIG. 2A is a diagrammatic view of a typical ultrasound image of thegastrointestinal tract of FIG. 1, showing the shadowing that resultsfrom air bubbles and air/fluid levels.

FIG. 2B is a typical photograph of an ultrasound image of thegastrointestinal tract of FIG. 1, showing the shadowing that results inthe stomach from air bubbles and air/fluid levels.

FIG. 2C is a typical photograph of an ultrasound image of thegastrointestinal tract of FIG. 1, showing the shadowing that results ina portion of the small intestine from air bubbles and air/fluid levels.

FIG. 3A is a diagrammatic view of an ultrasound image of thegastrointestinal tract of FIG. 1 after consumption of 750 ml of a 5%cellulose and 0.25% xanthan gum solution of the invention. Significantair/fluid levels and air bubbles are no longer present. Improvedvisualization of the gastrointestinal tract in general and improvedvisualization of the mucosa as distinguished from the tract lumen isobserved.

FIG. 3B is a photograph of an ultrasound image of the gastrointestinaltract of FIG. 1 after consumption of 750 ml of a 5% cellulose and 0.25%xanthan gum solution of the invention. Improved visualization of thegastrointestinal tract in general and improved visualization of themucosa as distinguished from the tract lumen is observed. In FIG. 3B, Sdenotes stomach, D denotes duodenum, and P denotes pancreas.

FIG. 4 is a graph showing the dB reflectivity of cellulose coated withsilicone and uncoated cellulose in vitro. The coated cellulose exhibitsa significantly better dB reflectivity.

FIG. 5 is a graph showing the dB reflectivity of cellulose fibers 18 μin length coated with varying amounts of silicone and simethicone invitro.

FIG. 6 is a graph showing the dB reflectivity of uncoated cellulosefibers of varying length at different concentrations of cellulose anddifferent transducer frequencies in vitro.

FIG. 7 is a graph showing the dB reflectivity of uncoated cellulosefibers of varying length at different concentrations of cellulose anddifferent transducer frequencies in vitro.

FIG. 8 is graph showing the dB reflectivity of cellulose fibers ofvarying length coated with 1% of different silicon compounds in vitro.

DETAILED DESCRIPTION OF THE INVENTION

Any of the wide variety of biocompatible polymers known in the art maybe employed in the medium and methods of the subject invention. The tenbiocompatible, used herein in conjunction with the term polymers, isemployed in its conventional sense, that is, to denote polymers that donot substantially interact with the tissues, fluids and other componentsof the body in an adverse fashion in the particular application ofinterest. As will be readily apparent to those skilled in the art, thereare numerous types of such polymers available.

The polymers useful in the present invention can be of either natural,semisynthetic or synthetic origin. As used herein, the term polymerdenotes a compound comprised of two or more repeating monomeric units,and preferably 10 or more repeating monomeric units. The termsemisynthetic polymer, as employed herein, denotes a natural polymerthat has been chemically modified in some fashion. Exemplary naturalpolymers suitable for use in the present invention include naturallyoccurring polysaccharides. Such polysaccharides include, for example,arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans,xylans (such as, for example, inulin), levan, fucoidan, carrageenan,galactocarolose, pectic acid, amylose, pullulan, glycogen, amylopectin,cellulose, dextran, pustulan, chitin, agarose, keratan, chondroitan,dermatan, hyaluronic acid, alginic acid, xanthan gum, starch and variousother natural homopolymer or heteropolymers such as those containing oneor more of the following aldoses, ketoses, acids or amines: erythrose,threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose,mannose, gulose, idose, galactose, talose, erythrulose, ribulose,xylulose, psicose, fructose, sorbose, tagatose, glucuronic acid,gluconic acid, glucaric acid, galacturonic acid, mannuronic acid,glucosamine, galactosamine, and neuraminic acid, and naturally occurringderivatives thereof. Exemplary semisynthetic polymers includecarboxymethylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, methylcellulose, and methoxycellulose.Exemplary synthetic polymers suitable for use in the present inventioninclude polyethylenes (such as, for example, polyethylene glycol,polyoxyethylene, and polyethylene terephthlate), polypropylenes (suchas, for example, polypropylene glycol), polyurethanes (such as, forexample, polyether polyurethane ureas), pluronic acids and alcohols,polyvinyls (such as, for example, polyvinyl alcohol, polyvinylchlorideand polyvinylpyrrolidone), nylon, polystyrene, polylactic acids,fluorinated hydrocarbons, fluorinated carbons (such as, for example,polytetrafluoroethylene), and polymethylmethacrylate, and derivativesthereof.

Preferably, the polymer employed is one which has a relatively highwater binding capacity. When used, for example, in the gastrointestinalregion, a polymer with a high water binding capacity binds a largeamount of free water, enabling the polymer to carry a large volume ofliquid through the gastrointestinal tract, thereby filling anddistending the tract. The filled and distended gastrointestinal tractpermits a clearer picture of the region. In addition, where imaging ofthe gastrointestinal region is desired, preferably the polymer employedis also one which is not substantially degraded within and absorbed fromthe gastrointestinal region. Minimization of metabolism and absorptionwithin the gastrointestinal tract is preferable, so as to avoid theremoval of the contrast agent from the tract as well as avoid theformation of gas within the tract as a result of this degradation.Moreover, particularly where gastrointestinal usage is contemplated, thepolymers are preferably such that they are capable of displacing air andminimizing the formation of large air bubbles within the polymercomposition.

In accordance with the invention, the polymers may be coated with and/orbe in admixture with a silicon containing compound. As used herein, thephrase silicon containing compound denotes both organic and inorganiccompounds containing the element silicon (Si). By admixture, it is meantthat the silicon containing compound is simply added to the polymercontaining medium, and is not chemically bound to the polymer. By theterm coated, it is meant that the silicon containing compound ischemically bound to the polymer. Suitable silicon containing compoundsinclude silicone, simethicones (such as simethicone and protectedsimethicone, the latter compound being polydimethylsiloxane with 4% to4.5% silicon dioxide), siloxanes (such as polysiloxane,polydimethyisiloxane, polymethylvinylsiloxane, polymethylphenolsiloxane,polydiphenylsiloxane, octamethylcyclotetrasiloxane and siloxane glycolpolymers), silanes (such as gamma-aminopropyltriethoxysilane,diethylaminomethyltriethoxysilane), silicon dioxide, siloxyalkylenepolymers, linear or cyclic silazanes (such as hexadimethylsilazane,hexamethyldisilazane, hexaphenylcyclotrisilazane andoctamethylcyclotetra-silazane), silyl compounds (such asN'N'-bis-(trimethylsilyl)acetamide andN-(dimethy(gamma-cyanopropyl)-silyl)-N-methylacetamide), and siliceousearth. Other suitable silicon compounds will be readily apparent tothose skilled in the art, and are described, for example, in Hertl etal., J. Phys. Chem., Vol. 75, No. 14, pp. 2182-2185 (1971). Such siliconcompounds may be easily prepared using conventional chemical synthesismethodology, such as is described in Chem. Abstracts, Vol. 69, No.61770x (1968), Vol. 70, No. 1164505k (1969), Vol. 74, No. 59904u (1971),Vol. 75, No. 9271v (1971), and Vol. 77, No. 37150q (1972), or may beobtained from various commercial sources. The silicon containingcompounds surprisingly serve a number of important functions in thecontrast medium, as both coating or admixed with the polymers, assistingin decreasing surface tension, minimizing foaming, increasingreflectivity, and/or lessening acoustic attenuation.

To prepare the biocompatible polymer coated with the silicon containingcompound, a polymer reactive with the desired silicon containingcompound is mixed therewith under conditions suitable for chemicalbonding of the polymer and the silicon compound. Such reactive polymersand suitable conditions will he readily apparent to one skilled in theart, once in possession of the present disclosure. Suitable proceduresinclude those described in Noll, Chemistry and Technology of Silicones,pp. 515-521 (Academic Press 1968), Hertl et al., J. Phys. Chem., Vol.75, No. 14, pp. 2182-2185 (1971), and Stark et al., J. Phys. Chem., Vol.72, No. 8, pp. 2750-2754 (1968), the disclosures of each of which areincorporated herein by reference in their entirety. Particularlyreactive with many of the silicon containing compounds are polymerscontaining free hydroxyl groups, such as cellulose and polyethyleneglycol.

Cellulose, a naturally occurring polymer that exhibits a high waterbinding capacity, when coated or admixed with a silicon containingcompound, is particularly preferred for use in the subject invention,especially when gastrointestinal usage is desired, resulting inexcellent echogenicity when ultrasound is applied. As a result of theirhigh water binding capacity, the cellulosic compounds pass through thegastrointestinal tract in a liquid medium distending the tract anddisplacing gas within the tract. In addition, since cellulose is notdegraded and absorbed within the tract, it does not result in theformation of any gases and is not removed from the tract along itsroute. Furthermore, cellulose is highly effective in displacing air andavoiding the formation of large air bubbles within the polymercomposition. Polyvinylpyrrolidone, polyethylene glycol, and otherpolyethylenes, when coated or admixed with a silicon containingcompound, are also preferable polymers, particularly wheregastrointestinal imaging is contemplated, functioning in a fashionsimilar to cellulose in binding water and distending thegastrointestinal tract, and resulting in highly improved visualizationof the bowel and adjacent structures by ultrasound. Polyethylene glycoland other polyethylenes are also very effective in preventing theformation of and in dispersing large gas bubbles. The silicon containingcompounds employed with the foregoing polymers serve to decrease surfacetension (thus allowing gas in the solution to escape more easily),minimize foaming, increase reflectivity, and/or lessen acousticattenuation in the resultant contrast media.

The polymers of the present invention may be employed as solids invarious shapes and forms, such as, for example, fibers, beads, and thelike. As those skilled in the art will recognize, the size of theindividual polymer fibers, beads, etc., can also vary widely.Preferably, however, the length of any polymer fibers and diameter ofany polymer beads is between about 0.1 and about 200 microns, morepreferably between about 5 and about 100 microns, most preferablybetween about 10 and about 20 microns. Fibers are preferred, and ingeneral, shorter fiber lengths have been found to possess betteracoustic properties and have better suspension uniformity than longerfiber lengths.

If desired, the polymers employed in the invention may be in liquidform, that is, liquid at physiological temperatures. The liquid polymerhas its own inherent unique echogenicity which allows differentiation ofbodily structures. Polyethylene glycol (PEG) of low molecular weightfunctions well in this regard (the lower molecular weight polymers beingliquid at physiological temperatures) as do fluorinated hydrocarbons. Asone skilled in the art will recognize, there are many polymers which areliquid at physiological temperatures and can be employed in thisfashion.

The polymers of the invention may be employed in an aqueous solution asa contrast medium for ultrasound imaging.

If desired, in addition, the polymer solutions may be employed inconjunction with an additional anti-gas agent. As used herein the termanti-gas agent is a compound that serves to minimize or decrease gasformation, dispersion and/or adsorption. A number of such agents areavailable, including antacids, antiflatulents and antifoaming agents.Such antacids and antiflatulents include, for example, activatedcharcoal, aluminum carbonate, aluminum hydroxide, aluminum phosphate,calcium carbonate, dihydroxyaluminum sodium carbonate, magaldratemagnesium oxide, magnesium trisilicate, sodium carbonate, loperamidehydrochloride, diphenoxylate, hydrochloride with atropine sulfate,Kaopectate™ (kaolin) and bismuth salts. Suitable antifoaming agentsuseful as anti-gas agents include polyoxypropylenepolyoxyethylenecopolymers, polyoxyalkylene amines and imines, branched polyamines,mixed oxyalkylated alcohols, sucroglycamides (celynols),polyoxylalkylated natural oils, halogenated silicon-containing cyclicacetals, lauryl sulfates, 2-lactylic acid esters of unicarboxylic acids,triglyceride oils. Particles of polyvinyl chloride may also function asanti-foaming agents in the subject invention. Of course, as thoseskilled in the art will recognize, any anti-gas agents employed must besuitable for use within the particular biological system of the patientin which it is to be used.

The polymer solutions may also, if desired, be employed with asuspending or viscosity increasing agent, referred to hereincollectively as a suspending agent. The phrase suspending agent, as usedherein, denotes a compound that assists in providing a relativelyuniform or homogeneous suspension of polymer through out the aqueoussolution. A number of such agents are available, including xanthum gum,acacia, agar, alginic acid, aluminum monostearate, unpurified bentonite,purified bentonite, bentonite magma, carbomer 934P,carboxymethylcellulose calcium, carboxymethylcellulose sodium,carboxymethylcellulose sodium 12, carrageenan, cellulose(microcrystalline), carboxymethylcellulose sodium, dextrin, gelatin,guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin,polyethylene oxide, polyvinyl alcohol, povidone, propylene glycolalginate, silicon dioxide, silicon dioxide colloidal, sodium alginate,and tragacanth.

Wide variations in the amounts of the polymer, silicon containingcompound, anti-gas agent, and suspending agent can be employed in thecontrast medium of the invention. Preferably, however, the polymer, whenemployed in solid form, is present in an aqueous solution in aconcentration of at least about 0.2% by weight, more preferably at leastabout 0.5% by weight, even more preferably at least about 1% by weight.Of course, as those skilled in the art would recognize, within theseparameters, the optimum polymer concentration will be influenced by themolecular weight of the polymer, its water binding capacity, itsparticular echogenicity, as well as other characteristics of theparticular polymer employed. In the case of cellulose, for example, thepolymer is most preferably present in a concentration of between about1% and about 5% cellulose by weight. When a medium to high molecularweight polyethylene glycol or polyvinylpyrrolidone is used as thepolymer, the concentration is most preferably between about 1% to about15% by weight. When the polymers are in liquid form, generally thepolymer is present in a somewhat higher concentration, such aspreferably in a concentration of at least about 10% by weight, morepreferably at least about 20% by weight, even more preferably at leastabout 30% by weight. For example, when liquid polyethylene glycol isemployed, the concentration is most preferably between about 10% andabout 90% by weight. Similarly, when a liquid perfluorocarbon is used,the concentration is most preferably between about 1% and about 90% byweight. With respect to the silicon containing compound, preferably theconcentration is between about 0.1% by weight and about 20% by weight,more preferably between about 0.5% by weight and about 10% by weight,most preferably between about 1% by weight and about 5% by weight,whether present as a coating (that is, chemically bound to the polymer)or as an admixture (that is, added to the polymer medium but notchemically bound to the polymer). Generally, because of an increasedability to remain in a homogeneous suspension, the lower amounts ofsilicon containing compound are preferred.

In a preferably embodiment, the contrast medium of the invention isdegassed, most preferably by either autoclaving the contrast medium, orby sonicating the contrast medium under vacuum (processes which forcesgas out of solution as well as sterilizes the product), and thenbottling the contrast medium under vacuum. The vacuum bottling is usedso as to keep any new gas bubbles from forming in the product. Thedegassing and vacuum bottling serves to enhance the ultimate ecogenicityand minimize shadowing when the contrast medium is employed in vivo.

If desired, an antimicrobial agent may be included in the contrastmedium to prevent bacterial overgrowth in the medium. Antimicrobialagents which may be employed include benzalkonium chloride, benzethoniumchloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridiniumchloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid,ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric nitrate, potassiumbenzoate, potassium sorbate, propylparaben, propylparaben sodium, sodiumbenzoate, sodium dehydroacetate, sodium propionate, sorbic acid,thimerosal, and thymol.

The present invention is useful in imaging a patient generally, and/orin specifically diagnosing the presence of diseased tissue in a patient.The imaging process of the present invention may be carried out byadministering a contrast medium of the invention to a patient, and thenscanning the patient using ultrasound imaging to obtain visible imagesof an internal region of a patient and/or of any diseased tissue in thatregion. By region of a patient, it is meant the whole patient, or aparticular area or portion of the patient. The contrast medium isparticularly useful in providing images of the gastrointestinal region,but can also be employed more broadly such as in imaging any bodycavities, or in other ways as will be readily apparent to those skilledin the art, such as in imaging the vasculature, liver, and spleen, andfor use in tissue characterization. The phrase gastrointestinal regionor gastrointestinal tract, as used herein, includes the region of apatient defined by the esophagus, stomach, small and large intestinesand rectum. By body cavities it is meant any region of the body havingan open passage, either directly or indirectly, to the externalenvironment, such regions including the gastrointestinal region, thesinus tract, the fallopian tubes, etc. The patient can be any type ofmammal, but most preferably is a human. Any of the various types ofultrasound imaging devices can be employed in the practice of theinvention, the particular type or model of the device not being criticalto the method of the invention.

As one skilled in the art would recognize, administration of thecontrast medium to the patient may be carried out in various fashions,such as orally, rectally or by injection. When the region to be scannedis the gastrointestinal region, administration of the contrast medium ofthe invention is preferably carried out orally or rectally. When otherbody cavities such as the fallopian tubes or sinus tracts are to bescanned, administration is preferably by injection. The useful dosage tobe administered and the particular mode of administration will varydepending upon the age, weight and the particular mammal and regionthereof to be scanned, and the particular contrast medium of theinvention to be employed. Typically, dosage is initiated at lower levelsand increased until the desired contrast enhancement is achieved. By wayof guidance, for gastrointestinal usage, about 10 ml of contrast mediumper kg weight of the patient is administered (that is, a 70 kg patientwould be administered about 700 ml of contrast medium). Variouscombinations of biocompatible polymers, silicon containing compounds,anti-gas agents, suspending agents, and other agents may be used tomodify the echogenicity or ultrasonic reflectance of thegastrointestinal contrast agent, as well as to achieve the desiredviscosity, gastric transit time, osmolality and palatability.

In carrying out the method of the present invention, the contrast mediumcan be used alone, or in combination with other diagnostic, therapeuticor other agents. Such other agents include flavoring or coloringmaterials, antioxidants, anticaking agents (to prevent caking onsettling), tonicity agents (to optionally adjust osmolality to beiso-osmotic), and wetting agents (to facilitate mixing of the componentsin the contrast medium). Flavoring materials include, for example,aspartame, dextrates, dextrose, dextrose excipient, fructose, mannitol,saccharin, saccharin calcium, saccharin sodium, sorbitol, sucrose, sugar(compressible), and sugar (confectioner's syrup). Coloring materialsinclude, for example, caramel and ferric oxide (e.g., red, yellow,black, or blends thereof). Antioxidants include, for example, ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide tocopherol, and tocopherols excipient.Anticaking agents include, for example, calcium silicate, magnesiumsilicate, and silicon dioxide (either colloidal or talc). Tonicityagents include, for example, dextrose, glycerin, mannitol, potassiumchloride, sodium chloride, and propylene glycol. Wetting agents include,for example, benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10,octoxynol 9, polyoxamer, polyoxyl 35 castor oil, polyoxyl 40hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate,sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, and tyloxapol. The foregoing additional agentsare conventional, and are described, for example, in the U.S.Pharmacopeia National Formulary, 22nd Revision, Jan. 1, 1990, MackPrinting Company, Easton, Pa.

The media of the present invention have been shown to be extremelyuseful as contrast enhancement agents in ultrasonic imaging,particularly in imaging of the gastrointestinal region.

Kits useful for ultrasonic imaging in accordance with the presentinvention comprise a contrast medium of the present invention, that is,an aqueous solution of at least one biocompatible polymer, wherein saidbiocompatible polymer is coated with and/or in admixture with at leastone silicon containing compound, in addition to conventional ultrasonicimaging kit components. Such conventional ultrasonic imaging kitcomponents are well known, and include, for example, anti-gas agents,suspending agents, flavoring materials, coloring agents andantioxidants, as described above.

A particularly preferred formulation of the contrast medium of thepresent invention useful in ultrasonic imaging, particularly of thegastrointestinal region, is a degassed solution comprised of thefollowing components:

(i) 0.5% by weight of an 18 micron fiber length cellulose polymer coatedwith 0.25% by weight of the silicon containing compound simethicone;

(ii) 500 ppm of the silicon containing compound simethicone in admixturewith the polymer in (i);

(iii) 100 ppm of the anti-gas agent lauryl sulfate;

(iv) 0.3% by weight xanthan gum; and

(v) optionally, the flavoring agent Vivonex™ (commercially availablefrom Norwhich Eaton Pharmaceutical Inc., Norwhich, N.Y.).

The present invention is further described in the following Examples. Inthe Examples which follow, the polymers described are in the form ofsolid fibers, with any sizes given denoting fiber length. The Examplesare not to be construed with as limiting the scope of the appendedClaims.

EXAMPLES Example 1

Surface tension, foaming and bubble formation was measured for variouscontrast media comprising biocompatible polymers, both (i) with coatingand/or in admixture with a silicon containing compound, and (ii) withoutcoating and/or in admixture with a silicon containing compound. In somecases anti-gas agents and/or suspending agents were included in thecontrast media tested. All samples were freshly degassed prior to use bysonication using a commercially available sonicator (Bransen, 2200Danbury, Conn.) under vacuum using a commercially available vacuum pump(Cole Parmer Model No. 7049-50, Chicago, Ill.).

Surface tension measurements were performed a 25° C. using a CSC-DuNouytensiometer No. 70535 (Fairfax, Va.). Degree of foaming was assessed byshaking the freshly degassed solutions in 50 cc plastic tubes (FisherScientific 05-539-8; Pittsburgh, Pa.). A volume of 25 cc of eachcontrast agent suspension was placed in the tube and the tubes werecapped. The tubes were then shaken vigorously for 60 seconds and thedegree of foaming was assessed at a time-point (60 seconds) after theshaking ceased. Foam was recorded on the scale of 0=no foam, 1=minimalfoam (about 1 mm), 2=moderate foam (about 2 to 3 mm), 3=severe foaming(more than 4 mm). The bubbles in the suspensions were assessed similarlyafter shaking but the bubbles were counted only within the suspensions,not as the foam which was determined by assessing the layer at the topof the suspension. Bubbles within the suspensions were assessed byexamining the bubbles and grading them as 0=no bubbles, 1=small bubbles(<1 mm diameter with very few bubbles), 2=medium bubbles (1-2 mmdiameter and few to moderate bubbles), and 3=large bubbles (>2 mmdiameter with many bubbles).

The data from the surface tension, foaming, and bubble measurements areset forth in the Tables I-III. As shown in Table I, cellulose functionsas a mild surfactant (that is, its surface tension is less than water),when the cellulose is prepared alone. When xanthan gum is added to thecellulose, this causes the mixture to lose some of its favorablesurfactant properties and the surface tension is similar to water.Polyethylene glycol (PEG 3350) has low surface tension and no foaming(but note in Example 2, that PEG has no appreciable reflectivity onultrasonic study). Methylcellulose caused appreciable foaming.Simethicone coated cellulose, on the other hand, has low surfacetension, no appreciable foaming, and no appreciable bubbles.

                  TABLE I                                                         ______________________________________                                        Effect of Simethicone/Silicone Coatings/Admixtures                            on Surface Tension, Foaming and Bubble Formation                                         Dynes/cm   Foam    Bubbles                                         ______________________________________                                        Deionized Water                                                                            73.5         0.0     0.0                                         18μ Cellulose                                                              1% cellulose 71.3         0.0     0.0                                         2% cellulose 71.2         0.0     0.0                                         18μ cellulose                                                              w/0.25% xanthan gum                                                           1% cellulose 72.7         0.0     1.0                                         2% cellulose 72.8         0.0     1.0                                         18μ cellulose                                                              w/0.05% xanthan gum                                                           1% cellulose 71.6         0.0     0.5                                         2% cellulose 72.0         0.0      0.05                                       18μ cellulose                                                                           70.6         0.0     0.0                                         1% simethicone coated                                                         0.25% xanthan gum                                                             18μ cellulose                                                                           70.3         0.0     0.0                                         1% silicone coated                                                            0.25% xanthan gum                                                             1% cellulose 61.0         0.0     0.0                                         1% silicone coated                                                            2% cellulose 61.8         0.0     0.0                                         1% silicone coated                                                            1% cellulose 62.0         0.0     0.0                                         1% simethicone coated                                                         2% cellulose 61.0         0.0     0.0                                         1% simethicone coated                                                         ______________________________________                                         Key:                                                                          Foam 0.0-3.0                                                                  Bubbles 0.0-3.0                                                               (for foam and bubbles, zero is the most favorable)                            Dynes (20.0-80.0) (for dynes, the lower the number, the better)          

                  TABLE II                                                        ______________________________________                                        Effect of Anti-Gas Agents                                                     on Surface Tension, Foaming and Bubble Formation                              of Simethicone/Silicone Coatings/Admixtures                                               Dynes/cm  Foam    Bubbles                                         ______________________________________                                        Sodium lauryl                                                                 sulfate w/                                                                    1% 18μ 1%                                                                  silicone coated                                                               cellulose w/                                                                  0.15% xanthan gum                                                             100 ppm       49.1        1.0     1.0                                         sodium                                                                        lauryl                                                                        sulfate                                                                       500 ppm       34.4        2.0     1.5                                         sodium                                                                        lauryl                                                                        sulfate                                                                       Sodium lauryl                                                                 sulfate w/                                                                    1% 18μ 1%                                                                  silicone coated                                                               cellulose w/                                                                  0.15% xanthan gum                                                             100 ppm       52.2        1.0     1.0                                         sodium                                                                        lauryl                                                                        sulfate                                                                       500 ppm       35.1        2.0     1.5                                         sodium                                                                        lauryl                                                                        sulfate                                                                       1000 ppm      32.9        0.0     0.0                                         Simethicone                                                                   w/500 ppm                                                                     sodium lauryl                                                                 sulfate w/                                                                    1% 18μ 1%                                                                  silicone coated                                                               cellulose w/                                                                  0.15% xanthan gum                                                             ______________________________________                                         Key:                                                                          Foam 0.0-3.0                                                                  Bubbles 0.0-3.0                                                               (for foam and bubbles, zero is the most favorable)                            Dynes (20.0-80.0) (for dynes, the lower the number, the better)          

                  TABLE III                                                       ______________________________________                                        Comparison of Various Polymer Compositions                                    in Surface Tension, Foaming and Bubble Formation                                            Dynes/cm Foam    Bubbles                                        ______________________________________                                        Deionized Water 73.5       0.0     0.0                                        18μ Cellulose                                                              1% cellulose    71.3       0.0     0.0                                        2% cellulose    71.2       0.0     0.0                                        Polyethylene Glycol                                                           (PEG3350) (Not Degassed)                                                      1% PEG          63.3       0.0     0.0                                        2% PEG          62.8       0.0     0.0                                        3% PEG          63.1       0.0     0.0                                        4% PEG          62.8       0.0     0.0                                        5% PEG          62.4       0.0     0.0                                        Polyethylene Glycol                                                           (PEG3350) (Degassed)                                                          1% PEG          62.3       0.0     0.0                                        2% PEG          62.1       0.0     0.0                                        3% PEG          61.6       0.0     0.0                                        4% PEG          61.5       0.0     0.0                                        5% PEG          61.2       0.0     0.0                                        18μ Cellulose                                                              w/0.25% Xanthan Gum                                                           1% cellulose    72.7       0.0     1.0                                        2% cellulose    72.8       0.0     1.0                                        3% cellulose    73.1       0.0     1.0                                        4% cellulose    72.8       0.0     1.0                                        5% cellulose    73.0       0.0     1.0                                        18μ Cellulose                                                              w/0.05% Xanthan Gum                                                           1% cellulose    71.6       0.0     0.5                                        2% cellulose    72.0       0.0     0.5                                        3% cellulose    71.7       0.0     0.5                                        4% cellulose    71.8       0.0     0.5                                        5% cellulose    71.9       0.0     0.5                                        Polyethylene Glycol                                                           (PEG3350)                                                                     w/1% 18μ Cellulose                                                         w/0.15% Xanthan Gum                                                           1% PEG          54.1       0.0     1.5                                        2% PEG          51.2       0.0     1.5                                        3% PEG          56.0       0.0     1.5                                        18μ Cellulose                                                                              70.6       0.0     0.0                                        1% Simethicone Coated                                                         w/0.25% Xanthan Gum                                                           18μ Cellulose                                                                              70.3       0.0     0.0                                        2% Silicone Coated                                                            0.25% Xanthan Gum                                                             Propylene Glycol                                                              w/1% 18μ 1% Silicone                                                       Coated Cellulose w/                                                           0.15% Xanthan Gum                                                             3% PG           61.8       0.0     1.0                                        5% PG           62.0       0.0     1.5                                        Sodium Lauryl Sulfate                                                         w/1% 18μ 1% Silicone                                                       Coated Cellulose                                                              w/0.15% Xanthan Gum                                                           100 ppm SLS     49.1       1.0     1.0                                        500 ppm SLS     34.4       2.0     1.5                                        Sodium Lauryl Sulfate                                                         w/2% Polyethylene Glycol                                                      (PEG3350)                                                                     w/1% 18μ 1% Silicone                                                       Coated Cellulose                                                              w/0.15% Xanthan Gum                                                           100 ppm SLS     51.5       1.0     1.5                                        500 ppm SLS     34.5       2.0     2.0                                        Sodium Lauryl Sulfate                                                         w/1% 18μ 1% Silicone                                                       Coated Cellulose                                                              w/0.15% Xanthan Gum                                                           100 ppm SLS     52.2       1.0     1.0                                        500 ppm SLS     35.1       2.0     1.5                                        Simethicone     32.9       0.0     1.0                                        w/500 ppm                                                                     Sodium Lauryl Sulfate                                                         w/1% 18μ Silicone                                                          Coated Cellulose                                                              w/0.15% Xanthan Gum                                                           1000 ppm simethicone                                                          1% 18μ 1% Simethicone                                                      Coated Cellulose                                                              w/500 ppm                                                                     Sodium Lauryl Sulfate                                                         w/1000 ppm Simethicone                                                        w/0.15% Xanthan Gum                                                           #1              30.8       1.5     1.5                                        #2              33.1       1.0     1.5                                        #3              33.2       1.0     1.5                                        #4              33.2       0.5     1.5                                        #5              32.9       0.5     1.5                                        #6              33.2       0.5     1.5                                        #7              32.8       0.5     1.5                                        #8              33.1       0.5     1.5                                        #9              32.1       0.5     1.5                                        Methyl Cellulose                                                              0.15%           54.6       2.0     0.0                                        0.25%           53.9       2.5     0.0                                        0.50%           54.1       2.5     0.0                                        1.00%           54.5       3.0     0.0                                        Hydroxyethyl Cellulose                                                        (Natrasol ™)                                                               0.15%           64.0       2.0     0.0                                        0.25%           56.1       1.5     0.5                                        0.50%           51.7       1.0     1.5                                        1.00%           50.4       0.5     2.5                                        Carrageenan                                                                   0.15%           72.9       0.0     0.0                                        0.25%           72.6       0.0     0.0                                        0.50%           72.8       0.0     0.5                                        Xanthan Gum                                                                   0.15%           72.8       0.0     0.5                                        0.25%           73.6       0.0     1.0                                        0.50%           73.1       0.0     1.0                                        1.00%           75.9       0.0     1.5                                        Carboxymethyl Cellulose                                                       0.15%           72.0       0.0     0.5                                        0.25%           72.4       0.0     1.0                                        0.50%           72.4       0.0     1.5                                        1.00%           73.3       0.0     2.0                                        Sodium Lauryl Sulfate                                                         100 ppm         51.4       1.0     0.0                                        200 ppm         48.6       1.5     0.0                                        300 ppm         35.7       2.0     0.0                                        400 ppm         29.8       2.5     0.0                                        500 ppm         29.5       3.0     0.0                                        Corn Starch                                                                   w/0.15% Xanthan Gum                                                           1% corn starch  73.0       0.0     0.0                                        3% corn starch  73.1       0.0     0.0                                        5% corn starch  73.1       0.0     0.0                                        Wheat (Cook-up) Starch                                                        w/0.15% Xanthan Gum                                                           1% wheat starch 72.2       0.0     1.5                                        3% wheat starch 71.0       0.0     2.0                                        5% wheat starch 69.7       0.0     2.5                                        Wheat (Instant) Starch                                                        w/0.15% Xanthan Gum                                                           1% wheat starch 59.9       0.0     2.0                                        3% wheat starch 56.7       0.0     2.0                                        5% wheat starch --         0.0     2.5                                        1% 18μ 1% Simethicone                                                                      37.6       0.0     0.0                                        Coated Cellulose                                                              w/0.30% Xanthan Gum                                                           (Keltrol RD ™)                                                             w/100 ppm                                                                     Sodium Lauryl Sulfate                                                         w/500 ppm Simethicone                                                         w/0.5% flavoring                                                              ______________________________________                                         Key:                                                                          Foam 0.0-3.0                                                                  Bubbles 0.0-3.0                                                               (for foam and bubbles, zero is the most favorable)                            Dynes (20.0-80.0) (for dynes, the lower the number, the better)          

Example 2

Velocity, acoustic impedance, dB reflectivity, and attenuation wasmeasured for various contrast media comprising biocompatible polymers,both (i) with coating and/or in admixture with a silicon containingcompound, and (ii) without coating and/or in admixture with a siliconcontaining compound.

The dB reflectivity of the different contrast agents was assessed withan Acoustic Imaging Model 5200 ultrasound scanner (Phoenix, Az.)equipped with Performance Software PFM. The transducers, either 5.0 or7.5 Mhz, were placed in the contrast agents and scanned. Prior toperforming each set of experiments the dB reflectivity was standardizedto a known reference phantom. For the dB reflectivity measurements onthe Acoustic Imaging 5200, a tissue mimicking phantom was used as areference. The tissue mimicking phantom is made by Nuclear Associates.The gain was set to -53.5 dB. The dB reflectivity measurements were madeby selecting a region of interest on the CRT monitor and reading themean dB reflectivity in that region. Quantitative measurements ofsamples were obtained on a benchtop acoustic lab custom built byImaR_(x), (Tucson, Az.), consisting of a Panemetric (Waltham, Mass.)5052PR ultrasonic pulser/receiver, LeCroy (Chestnut Ridge, N.Y.) 9410dual channel digital oscilloscope with a waveform processing package andcapabilities of Fast Fourier Transform and Krautkramer Branson(Lewistown, Pa.), F-style, Gamma-HP series transducers. Data wasobtained using the pulse-echo technique. The returned echoes weremeasured with the appropriate time delays and the power average of thewaveform was calculated. The frequencies of the transducers used were2.25, 3.25, 5.0, 7.5 and 10 mHz. The ultrasonic waves were reflectedfrom a solution/air interface reflected from a solution/air interface.Parameters of velocity, acoustic impedance, attenuation andtransmittance were assessed.

As shown by the data, cellulose with simethicone coating has both goodreflectivity and very high transmission (that is, less acousticattenuation) than plain cellulose. Note also that polyethyleneglycol hasmuch lower reflectivity than cellulose.

FIGS. 4-8 show the dB reflectivity from the measurements made on thephantoms with the Acoustic Imaging Ultrasound machine. As shown by thesefigures, for plain cellulose the shorter fibers (e.g. 18 through 35micron) have higher reflectivity than the longer cellulose fibers. Notethat the silicone coated cellulose has higher reflectivity than theuncoated fibers.

Example 3

Hexamethyldisilazane (1,1,1,3,3,3-hexamethyldisilazane) (2 g),commercially available from Aldrich Chemical Company, Milwaukee, Wis.,was added to 10 g of ethyl alcohol (200 proof dehydrated alcohol, U.S.P.punctilious). The hexamethyldisilazane and ethyl alcohol mixture wasthen added drop by drop to 28.5 g of cellulose (fiber lengths 18 μ, 22μ, and 35 μ, respectively) in a flask. The mixture was stirred andheated at a temperature of about 60° C. in a vacuum oven. After theethyl alcohol was evaporated, the flask was placed into a laboratoryoven and heated from about 60° C. to about 140° C. for about two hoursand then cooled, resulting in hexamethyldisilazane coated cellulose(also referred to herein generally as silylated cellulose).

Example 4

Silicone (in oil form) (2 g), commercially available from AldrichChemical Co. Inc., was added to 10 g of toluene. The silicone andtoluene mixture was then added drop by drop to 28.5 g of cellulose in aflask. The mixture was stirred and heated at a temperature of about 60°C. in a vacuum even. After the toluene was evaporated, the flask wasplaced into a laboratory oven and heated from about 60° C. to about 140°C. for about two hours and then cooled, resulting in silicone coatedcellulose.

Example 5

A solution containing about 15% by weight polyethylene glycol fibershaving a molecular weight of about 8000 was prepared in deionized water.The solution was then mixed with a gas and the solution was scanned invitro by ultrasound.

The polyethylene glycol polymer solution was found to improve gasdissipation and render a good image on in vitro scanning.

Example 6

Three solutions containing about 5% by weight cellulose fibers havingvarying fiber lengths of cellulose of about 22, 60, and 110 microns,respectively, and each containing about 0.25% xanthan gum were preparedin distilled water. A fourth solution containing about 5% by weightdextran beads of about 20 micron diameter was prepared in distilledwater. The solutions were scanned in vitro by ultrasound at constantgain settings using a 5 megahertz transducer (approximately a 300 micronwave length in aqueous media).

The 20 micron diameter dextran bead solution had the highestechogenicity of the four solutions, with the 22 micron fiber lengthcellulose solution having the next highest echogenicity.

Example 7

A solution containing about 5% by weight cellulose fibers having a fiberlength of about 22 microns and about 0.25% by weight xanthan gum wasprepared in deionized water. Approximately 750 ml of the solution wasthen administered orally to a mammal, and ultrasonic imaging of thegastrointestinal tract was performed.

Distention of the gastrointestinal tract and good visualization of thegastrointestinal region was achieved. Excellent visualization of themucosal surfaces of the stomach and intestine was also achieved.

Example 8

A solution containing about 4% by weight cellulose fibers having a fiberlength of about 22 microns and about 2 g of activated charcoal indeionized water was prepared. Approximately 750 ml of the solution wasthen administered orally to a mammal and ultrasonic imaging of thegastrointestinal tract was performed.

Ultrasonic imaging provided good visualization of the tract and mucosalsurfaces.

Example 9

A solution containing about 5% by weight cellulose fibers having a fiberlength of about 22 microns and about 0.25% by weight xanthan gum wasprepared in deionized water. To this solution, about 2.0 g ofsimethicone was added and the solution was mixed. Approximately 750 mlof the solution was then administered orally to a mammal, and ultrasonicimaging of the gastrointestinal tract was performed.

Ultrasonic imaging provided good visualization of the tract and mucosalsurfaces. In addition, improved removal of gas bubbles from thegastrointestinal tract was observed.

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended Claims.

What is claimed is:
 1. A method of providing an image of an internalregion of a patient comprising (i) administering to the patient acontrast medium comprising an aqueous suspension of at least onebiocompatible polymer, wherein said biocompatible polymer is coated withat least one silicon containing compound, and (ii) scanning the patientusing ultrasonic imaging to obtain visible images of the region.
 2. Amethod of claim 1 wherein the region is the gastrointestinal region. 3.A method of claim 1 wherein the region is a body cavity.
 4. A method fordiagnosing the presence of diseased tissue in a patient comprising (i)administering to the patient a contrast medium comprising an aqueoussuspension of at least one biocompatible polymer, wherein saidbiocompatible polymer is coated with at least one silicon containingcompound, and (ii) scanning the patient using ultrasonic imaging toobtain visible images of any diseased tissue in the patient.
 5. A methodof claim 4 wherein the scanning is of the gastrointestinal region of thepatient.
 6. A method of claim 4 where the scanning is of a body cavityof the patient.
 7. A method of claim 1 wherein the biocompatible polymeris in admixture with at least one silicon containing compound.
 8. Amethod of claim 1 wherein the polymer is a natural polymer or a modifiednatural polymer.
 9. A method of claim 1 wherein the polymer is apolysaccharide.
 10. A method of claim 1 wherein the polymer is celluloseor a modified cellulose polymer.
 11. A method of claim 1 wherein thepolymer is selected from the group consisting of arabinans, fructans,fucans, galactans, galacturonans, glucans, mannans, xylans, levan,fucoidan, carrageenan, galactocarolose, pectic acid, amylose, pullulan,glycogen, amylopectin, cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, methyl cellulose,methoxycellulose, dextran, pustulan, chitin, agarose, keratan,chondroitin, dermatan, hyaluronic acid, alginic acid, xanthan gum, andpolysaccharides containing at least one aldose, ketose, acid or amineselected from the group consisting of erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose,idose, galactose, talose, erythrulose, ribulose, xylulose, psicose,fructose, sorbose, tagatose, glucuronic acid, mannuronic acid,glucosamine, galactosamine, and neuraminic acid.
 12. A method of claim 1wherein the polymer is cellulose.
 13. A method of claim 1 wherein thesilicon containing compound is a polysiloxane compound.
 14. A method ofclaim 1 wherein the silicon containing compound is selected from thegroup consisting of silicone, simethicone, protected simethicone,polysiloxane, polydimethylsiloxane, polymethylvinyl-siloxane,polymethylphenolsiloxane, polydiphenylsiloxane,octamethylcyclotetrasiloxane, siloxane glycol polymer,gamma-aminopropyltriethoxysilane, diethylaminomethyltri-ethoxysilane,silicon dioxide, siloxyalkylene polymer, hexadimethylsilazane,hexamethyldisilazane, hexaphenyl-cyclotrisilazane,octamethylcyclotetrasilazane, N'N'-bis-(trimethylsilyl)acetamide,N-(dimethy(gamma-cyanopropyl)-silyl)-N-methylacetamide), and siliceousearth.
 15. A method of claim 1 wherein the silicon containing compoundis simethicone.
 16. A contrast medium of claim 1 wherein the siliconcontaining compound is anα-(trimethyl-silyl)-ω-methylpoly(oxy-(dimethylsilylene)) compound.
 17. Amethod of claim 1 wherein the contrast medium is an aqueous suspension,the biocompatible polymer is cellulose, and the polymer is coated withsimethicone.
 18. A method of claim 1 wherein the contrast medium is anaqueous suspension, the biocompatible polymer is cellulose, and thepolymer is coated with anα-(trimethyl-silyl)-ω-methylpoly(oxy-(dimethylsilylene)) compound.
 19. Amethod of claim 1 further comprising at least one compound selected fromthe group consisting of anti-gas agents and suspending agents.
 20. Amethod of claim 17 further comprising xanthan gum and a compoundselected from the group consisting of lauryl sulfate and apolyoxyethylene compound.
 21. A method of claim 18 further comprisingxanthan gum and a compound selected from the group consisting of laurylsulfate and a polyoxyethylene compound.